Roles of thioredoxin reductase 1 and APE/Ref-1 in the control of basal p53 stability and activity.

The p53 protein is redox-sensitive in vitro but in vivo effectors of this sensitivity are not known. In yeasts deficient for thioredoxin (Trx) reductase (TRR), p53 accumulates in an inactive, oxidized form, suggesting a role for TRR-Trx in controlling p53. In mammalian cells, p53 binds to redox factor-1 (APE/Ref-1), an ...
enzyme containing an abasic endonuclease domain involved in base excision repair, and a thiol reductase domain recycled by Trx and involved in regulating the transcription factor AP-1. To evaluate the role of TRR and APE/Ref-1 in p53 regulation, we have abrogated their expression using RNA interference in cell lines expressing wild-type p53. Inhibition of TRR resulted in accumulation of oxidized Trx and increased levels and DNA-binding activity of p53, with no phosphorylation of Ser15 or Ser20. In contrast, inhibition of APE/Ref-1 accelerated p53 protein turnover, resulting in a decrease in p53 levels and activity. However, inhibition of either TRR or APE/Ref-1 did not prevent activation and accumulation of p53 in response to DNA-damage by doxorubicin. When both factors were inhibited, basal levels of p53 were restored. These results suggest that TRR-Trx and APE/Ref-1 cooperate in the control of basal p53 activity, but not in its induction by DNA-damage.
Mesh Terms:
Breast Neoplasms, Cell Line, Tumor, DNA Damage, DNA Primers, DNA-(Apurinic or Apyrimidinic Site) Lyase, Female, Gene Expression Regulation, Neoplastic, Genes, p53, Humans, Phosphorylation, Reverse Transcriptase Polymerase Chain Reaction, Thioredoxin Reductase 1, Thioredoxin-Disulfide Reductase, Transcription Factor AP-1, Tumor Suppressor Protein p53
Oncogene
Date: Jun. 02, 2005
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